U.S. patent application number 14/412204 was filed with the patent office on 2015-06-25 for apparatus for the homogenization and separation of samples.
This patent application is currently assigned to KTB TUMORFORSCHUNGSGESELLSCHAFT MBH. The applicant listed for this patent is ANDREAS HETTICH GAMBH & CO. KG, KTB TUMORFORSCHUNGSGESELLSCHAFT MBH. Invention is credited to Klaus-Gunter Eberle, Anke Lenz, Ulrich Massing, Vittorio Ziroli.
Application Number | 20150174539 14/412204 |
Document ID | / |
Family ID | 48856588 |
Filed Date | 2015-06-25 |
United States Patent
Application |
20150174539 |
Kind Code |
A1 |
Eberle; Klaus-Gunter ; et
al. |
June 25, 2015 |
APPARATUS FOR THE HOMOGENIZATION AND SEPARATION OF SAMPLES
Abstract
The invention relates to an apparatus for the homogenization and
separation of media (10), comprising a centrifuge (40, 70) having a
centrifuge rotor (14, 44, 74) which can be rotated about a motor
axis (A) of a centrifuge motor (12, 42, 72) and which includes a
rotor body, connected to which is at least one rotation unit (16,
48, 80) in such a way that it is additionally adapted to be
rotatable about an axis of rotation of a rotation unit, which axis
is different from the motor axis (A), and that it can be driven via
a rotation unit drive, with means being provided which can be used
to set at least two different rotation speeds of the rotation unit
(16, 48, 80), and furthermore the rotation unit (16, 48, 80) has
toothing (8) on its periphery by which the rotation unit (16, 48,
80) can be driven. The invention is characterized in that the
rotation unit drive comprises toothing which is associated with the
centrifuge motor.
Inventors: |
Eberle; Klaus-Gunter;
(Tuttlingen, DE) ; Lenz; Anke; (Leibertingen,
DE) ; Massing; Ulrich; (Merzhausen, DE) ;
Ziroli; Vittorio; (March, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ANDREAS HETTICH GAMBH & CO. KG
KTB TUMORFORSCHUNGSGESELLSCHAFT MBH |
TUTTLINGEN
FREIBURG |
|
DE
DE |
|
|
Assignee: |
KTB TUMORFORSCHUNGSGESELLSCHAFT
MBH
FREIBURG
DE
ANDREAS HETTICH GMBH & CO. KG
TUTTLINGEN
DE
|
Family ID: |
48856588 |
Appl. No.: |
14/412204 |
Filed: |
July 2, 2013 |
PCT Filed: |
July 2, 2013 |
PCT NO: |
PCT/EP2013/063963 |
371 Date: |
December 30, 2014 |
Current U.S.
Class: |
366/218 |
Current CPC
Class: |
B01F 9/0003 20130101;
B29B 7/106 20130101; B01F 2009/0067 20130101; B01F 2015/0011
20130101; B01F 9/0001 20130101; B04B 5/02 20130101; B01F 2015/00623
20130101 |
International
Class: |
B01F 9/00 20060101
B01F009/00 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 2, 2012 |
DE |
10 2012 105 819.9 |
Claims
1. An apparatus for the homogenization and separation of media (10)
comprising a centrifuge (40, 70) having a centrifuge rotor (14, 44,
74) which can be rotated about a motor axis (A) of a centrifuge
motor (12, 42, 72) and which includes a rotor body, connected to
which is at least one rotation unit (16, 48, 80) in such a way that
it is additionally adapted to be rotatable about an axis of
rotation of a rotation unit which is different from the motor axis
(A), and that it can be driven via a rotation unit drive, with
means being provided which can be used to set at least two
different rotation speeds of the rotation unit (16, 48, 80), and
furthermore the rotation unit (16, 48, 80) has toothing (8) on its
periphery by which the rotation unit (16, 48, 80) can be driven,
said rotation unit drive comprises toothing which is associated
with the centrifuge motor.
2. The apparatus of claim 1, characterized in that the drive of the
rotation unit is designed such that at least one transmitting gear
(54a, 54b) is provided which meshes with toothing (50a, 50b) which
is firmly mounted with respect to the rotating motor axle (A), and
with the toothing (18) provided on the rotation unit (16, 48,
80).
3. The apparatus of claim 2, characterized in that the transmitting
gear is provided in the form of a pair (52) of gears, of which a
first transmitting gear (54) meshes with toothing (50)
non-rotatably mounted with respect to the motor axis (A), and a
second transmitting gear (56) meshes with the toothing (18) on the
rotation unit.
4. The apparatus of claim 1, characterized in that the
non-rotatably mounted toothing (50) can be placed over the
centrifuge axle (A) and attached to the centrifuge motor housing
(20).
5. An apparatus for the homogenization and separation of media (10)
comprising a centrifuge (40, 70) having a centrifuge rotor (14, 44,
74) which can be rotated about a motor axis (A) of a centrifuge
motor (12, 42, 72) and which includes a rotor body, connected to
which is at least one rotation unit (16, 48, 80) in such a way that
it is additionally adapted to be rotatable about an axis of
rotation of a rotation unit which is different from the motor axis
(A), and that it can be driven via a rotation unit drive, with
means being provided which can be used to set at least two
different rotation speeds of the rotation unit (16, 48, 80), and
furthermore the rotation unit (16, 48, 80) has toothing (8) on its
periphery by which the rotation unit (16, 48, 80) can be driven,
said at least one rotation unit motor (76) which is independent of
the centrifuge motor (12, 42, 72) is provided as the rotation unit
drive and is mounted on the centrifuge rotor.
6. The apparatus of claim 5, characterized in that the rotation
unit motor (76) is coaxially mounted with respect to the motor axis
(A) on the centrifuge rotor (14, 44, 74).
7. The apparatus of claim 6, characterized in that for each
rotation unit (16, 48, 80) one rotation unit motor each is
provided.
8. The apparatus according to claim 5, characterized in that the
transmission of energy and/or signals to the rotation unit motor
(76) is wireless.
9. The apparatus according to claim 5, characterized in that the
transmission of energy and/or signals to the rotation unit motor
(76) is accomplished using sliding contacts.
10. The apparatus according to claim 5, characterized in that the
rotation unit motor (76) is in the form of a stepper motor.
11. An apparatus for the homogenization and separation of media
(10), comprising a centrifuge (40, 70) having a centrifuge rotor
(14, 44, 74) adapted to be rotatable about a motor axis (A) of a
centrifuge motor (12, 42, 72) and including a rotor body to which
at least one rotation unit (16, 48, 80) can be attached in such a
way that it can be rotated about a rotation axis of a rotation
unit, secondary axis of rotation, which is different from the motor
axis (A), with a drive of a rotation unit being provided for
generating the rotary motion of the rotation unit (16, 48, 80),
said rotation unit (16, 48, 80) being accommodated in a recess (30,
46, 84) having a closed base and provided within the rotor body,
and, a bearing (24, 26) is provided for supporting the rotation
unit, which bearing is disposed below the position of the centre of
gravity of the centrifuge container during centrifugation.
12. The apparatus according to claim 1, characterized in that the
rotation unit (16, 48, 80) is provided in the form of a
turntable.
13. The apparatus according to claim 1, characterized in that the
rotation unit (16, 48, 80) comprises a holding fixture (96) into
which material to be centrifuged or a centrifuge container
containing material to be centrifuged can be placed.
14. The apparatus of claim 12, characterized in that a reduction
means is provided which can be placed in the holding fixture (96),
and a centrifuge container can in turn be placed into said
reduction means.
15. The apparatus according to claim 1, characterized in that the
holding fixture (96) is provided in the form of a cage and has
recesses (30, 46, 84), in particular in a circumferential direction
thereof.
16. A method of operating an apparatus according to claim 1,
characterized in that sample parameters are measured and the speed
of rotation is set as a function of the sample parameters.
17. The method of claim 16, characterized in that the sample
parameters measured are viscosity and/or temperature.
Description
[0001] The invention relates to an apparatus for the dual
centrifugation of samples.
[0002] Dual centrifugation (DC) is a process in which a sample is
rotated about a main axis of rotation whilst simultaneously
rotating about a secondary axis of rotation, which secondary axis
of rotation may intersect the sample at any position thereof and
may also be located outside the sample.
[0003] For this reason, a dual centrifugation apparatus comprises,
in addition to a main axis of rotation, at least one additional
axis of rotation, i.e. a secondary axis of rotation, about which a
sample can be rotated. Typically, a means for receiving and holding
a sample (sample holder) is rotated about the secondary axis of
rotation.
[0004] Processes which are performed using a dual centrifugation
apparatus, i.e. exploiting the interaction of two rotary motions,
are referred to as dual centrifugation processes (DC processes).
Such processes can be performed more efficiently than conventional
processes as they involve the use of a dual centrifugation
apparatus. Important examples include homogenization, mixing,
tissue disruption.
[0005] US 2002/0172091 A1 relates to a dual asymmetric centrifuge
for the production of food, in particular characterized by
precisely one centrifuge container which can be rotated about a
container axis and is rotationally symmetrical with respect to the
latter. The container is mounted on the distal end of a rotating
rotor arm. A shaft connects said container to a drive mechanism
which is mounted on the end of the centrifuge rotor which is
opposite said container. The speed of rotation of said container is
set as a function of the centrifuge speed and at an invariable
ratio. This has the disadvantage that samples which--owing to their
specific sample properties--require a certain ratio of main
rotation to reverse rotation that does not correspond to the ratio
prevailing in this apparatus, cannot be processed. Furthermore,
this apparatus cannot be used for pure centrifugation purposes.
[0006] Another simple type of dual asymmetric centrifugation which
only includes one secondary axis of rotation is described in US
2003/0214878 A1.
[0007] This document discloses an apparatus for mixing fluid
dispersions, in which a container is mounted to be rotatable about
a first axis which is inclined with respect to a further axis of
rotation that is connected to the container, i.e. a secondary axis
of rotation. The first axis of rotation is driven by a motor. The
second axis of rotation is connected to a wheel which is pressed
against a solid contact surface. Rotation of the rotor arm will
result in the wheel connected to the container and the container
axis being guided along the contact surface which is stationary
with respect to both the rotor arm and the container axis. This
results in additional rotation of the container about the secondary
axis of rotation which thus makes the speed of rotation of the
container directly dependent on the centrifuge motor speed.
[0008] Disclosed in U.S. Pat. No. 5,352,037 is a dual symmetrical
centrifuge including centrifuge containers mounted on a centrifuge
rotor. Said centrifuge containers are rotationally symmetrical and
mounted on the rotor arm so as to be rotatable about their axis of
rotation (secondary axis of rotation). The containers are driven by
a transmission coupled to said rotor. Consequently, the
transmission ratio is fixed. As a result, the container speed of
rotation is directly related to the centrifuge motor speed. This
apparatus can neither be used for homogenization nor for pure
centrifugation as this apparatus is not capable of realizing the
long centrifugation time at a high speed of rotation.
[0009] U.S. Pat. No. 1,011,929 discloses an apparatus for mixing
and separating media, which apparatus also includes a container
that is rotatable about a main rotor. The containers in turn are
mounted about an axis of rotation which is different from the main
rotor, and are connected to the main rotor via a transmission.
Separation can only be performed after sieve-like structures have
been placed in the containers.
[0010] According to the present state of the art, it is possible to
use a dual centrifuge for the purposes of mixing and homogenization
of sample material.
[0011] However, the prior art apparatuses do not allow the
separation of samples to be performed by means of centrifugation. A
prior art dual centrifuge is not suited for use as a mere
centrifuge as it will neither be able to survive the required
duration of a centrifugation process nor will it withstand the high
centrifugal and/or centripetal forces undamaged.
[0012] DE 101 43 439 A1 discloses a dual asymmetric centrifuge for
mixing sample material in which a secondary axis of rotation is
driven by a V belt, similar to what is described in US 2002/0172091
A1. Furthermore, it is described in this document that the ratio of
main rotation to secondary rotation can be adjusted as required for
the material to be centrifuged without making any major structural
changes to the apparatus. This is achieved in particular by
adapting the diameters of the driving and driven rollers. In this
apparatus, the axle connecting the driven roller to an angular gear
is provided with a rotary shaft seal to prevent lubricant leakage.
This is disadvantageous in that, after long hours of operation of
the apparatus, this seal will become leaky, and lubricant will leak
out as a result of the centrifugal and/or accelerating forces
prevailing in the area of the seal. This may damage the gear unit
and also lead to the centrifuge interior becoming contaminated with
lubricant. This problem occurs especially as the bearing heats
up--which limits operation times of the apparatus to a maximum of
30 minutes.
[0013] Disclosed in JP 2009119587 A is a mixing apparatus
comprising a centrifuge motor and a centrifuge rotor, with
containers being rotatably mounted on the rotor and supported on
the rotor by means of a rotation unit featuring toothing on its
circumference. Reverse rotation is effected by a shaft of a
rotation unit drive which is housed in a hollow shaft within a
centrifuge motor.
[0014] It is the object of the invention to provide an apparatus
for dual centrifugation which is capable not only of the
homogenization, but also of the separation of sample material, and
which can be better adjusted to the requirements of the sample
material.
[0015] Contrary to a mere mixing process, homogenization requires
the sample material to be exposed to clearly higher forces so as to
ensure the splitting of particles required for the homogenization
of especially liquid media such as emulsions or dispersions.
Consequently, a high speed of rotation of the centrifuge rotor is
required for the application of such high forces.
[0016] This object is accomplished by the preamble of claim 11 in
combination with its characterizing features.
[0017] According to a first aspect of the invention, an apparatus
for the homogenization and separation of media in a known manner
comprises a centrifuge which includes a centrifuge rotor capable of
rotating about a motor axle of a centrifuge motor, said rotor
having a rotor body on which at least one rotation unit can be
mounted in such a way that it can be rotated about an axis of
rotation of a rotation unit which is different from the motor axis,
which rotation unit is provided with a drive for generating the
rotary motion of the rotation unit.
[0018] According to the invention, the rotation unit is
accommodated in a recess provided in the rotor body and which is
closed at the bottom. In addition, a bearing is provided for
supporting the rotation unit, which bearing is disposed below the
position of the centre of gravity of the centrifuge container
during centrifugation.
[0019] For this reason, a potential receptacle portion of the
rotation unit is substantially located outside the rotor body. As a
consequence, the receptacle portion is subjected to the air flows
created during rotation of the rotor. This allows for improved
cooling of the samples accommodated in the receptacle portion.
[0020] The fact that the recess is closed at its bottom ensures
that any lubricant leaking from a bearing will be contained within
said recess for the entire centrifugation time and will thus be
available in the area of the bearing. The bearing will thus be well
lubricated during the entire operation period, thus preventing
seizure.
[0021] The design according to the invention thus yields a dual
centrifuge which will ensure a sufficiently long operation time
and, at the same time, appropriately high centrifugal forces for
centrifugation purposes as well as for efficient homogenization
processes. Consequently, in addition to simple blending and mixing
procedures, this apparatus will also be capable of performing
separation and homogenization procedures.
[0022] Combining the high forces required for homogenization with a
reverse rotation of the centrifuge containers and long run times is
not feasible with the prior art apparatuses. However, this can be
accomplished using the specific mounting of the present
invention.
[0023] Preferably, lubricant can be filled into the recess and
received in it in such a way that it will also remain within the
recess during centrifugation.
[0024] The fact that lubricant can be filled into the recess
separately ensures improved lubrication as opposed to cases in
which lubricant exits a bearing. In particular, the lubricant is
provided in the form of a homogeneous lubricant in order to prevent
its separation during centrifugation. Preferably oil can be used as
a lubricant.
[0025] In a particularly preferred embodiment, the rotation unit is
connected to the centrifuge rotor via at least one roller bearing.
Roller bearings constitute a particularly effective type of
bearing.
[0026] If the rotation unit is supported by roller bearings, in
particular ball bearings, relative to the centrifuge rotor, filling
the recess with lubricant is considered advantageous here as well.
The filling level may be chosen such that at least part of the
existing roller bearings will be thinly covered with lubricant.
[0027] Preferably, the rotation unit will be supported with respect
to the rotor body in such a way that the rotation unit is connected
to the inner ring of the bearing and the rotor body is connected to
the outer ring of the bearing. In addition, the rotor body can
enclose the bearing at least partially at the bottom of the
bearing.
[0028] Configuring the bearing in this way ensures that the
lubricant contained in the bearing and which will also be exposed
to centrifugal forces and thus be urged out of the bearing will be
retained within the centrifuge rotor. In this way the lubricant
will collect in the tray inside the rotor body. The centrifugal
forces occurring will cause any lubricant that has leaked out to be
collected on the radially exterior wall of the tray. A bearing
configuration in which the outer ring of the bearing contacts the
radially exterior wall of the recess will facilitate lubrication of
such a bearing during centrifugation and thus require less
lubricant to be used.
[0029] In yet another advantageous embodiment the bearing is
provided in the form of an angular contact bearing. This allows
optimal absorption of forces during centrifugation. Advantageous
settings for an angular contact bearing will be obtained at an
angular range of between 5.degree. and 85.degree., preferably
between 25.degree. and 65.degree., with between 40.degree. and
50.degree. being the particularly preferred range. These angles may
be chosen irrespective of the scope of application.
[0030] The angular contact bearing is designed for an angle of in
particular 45.degree.. This embodiment takes account of the
installation location of the rotation unit, in particular in the
case of an angle rotor.
[0031] In yet another advantageous embodiment, the rotation unit
may be connected to the rotor body via a shaft extending into the
latter. In particular, due to the fact that the bearing is
encompassed and accommodated within the rotor body, the bearing can
be supplied with additional lubricant. In this way it can be
ensured that the bearing will constantly be covered with lubricant,
at least on an external side thereof, thus prevent bearing seizure.
As the lubricant will remain within the recess, this will also
prevent contamination of the environment.
[0032] The rotation unit inserted in the bearing may be connected
to a holding fixture.
[0033] Preferably, the rotation unit may be of a diameter which
corresponds to approximately half of the diameter of the rotor. A
range of between 30% and 45% of the rotor diameter is considered
particularly suitable. This will yield a high degree of flexibility
in the design of the holding fixtures. In particular, the axis of
rotation of the rotation unit will be inclined with respect to the
main axis of the rotor.
[0034] The rotation unit supported by the bearing may be provided
as an integral unit with a holding fixture, in particular a cage.
The holding fixture preferably has recesses, which results in
improved dissipation of the heat generated during operation. When
samples are processed according to the prior art, temperatures of
up to 80.degree. may arise in a sample container inserted in the
holding fixture, thus making it impossible to process
temperature-sensitive samples. The recesses provided in the walls
of the holding fixture allow circulating air flows to be
advantageously used during rotation in order to cool the sample
containers and/or the samples contained in them. This has the
advantage that temperature-sensitive samples can thus also be
processed.
[0035] As an alternative, a holding fixture, in particular a cage,
may be releasably mounted on the rotation unit. A sample container
containing material to be centrifuged can be inserted into the
holding fixture.
[0036] The holding fixture may also be designed as a centrifuge
container which can be releasably mounted on the rotation unit. In
this case, the material to be centrifuged will be introduced
directly into the holding fixture.
[0037] Furthermore, reduction means may be provided which, on the
one hand, can be placed in the holding fixture, and on the other
hand provides a holding function for one or plural centrifuge
containers. The use of reduction means for the relatively large
diameter of the rotation unit makes it possible to use the
apparatus according to the invention with a wide variety of
vessels, a large number of sample containers, and sample containers
of an elongated design, such as Falcon.RTM. tubes.
[0038] The design, in particular the size and geometry, of the
reduction means has been adapted to the centrifuge containers
provided and to the holding fixture.
[0039] The reduction means may also be connected directly to the
rotation unit, without any holding fixture in between.
[0040] The reduction means in particular features recesses in its
circumference. This leads to improved dissipation of the heat
created due to the high rotation speeds from the sample
container.
[0041] Preferably toothing is provided on the rotation unit which
is adapted to mesh with a gear for the purpose of transmitting the
rotary motion.
[0042] The fact that the rotary motion is transmitted by means of a
gear or a gear drive allows a dual centrifugation process to be
performed continuously over a long period of time.
[0043] The gear made to mesh with the rotation unit may be a drive
gear or a transmitting gear.
[0044] A drive gear is characterized by the fact that there is a
relative rotary motion between the drive gear and the centrifuge
rotor. This is also the case with a stationary gear.
[0045] This for example allows the rotary motion of the centrifuge
rotor to be transmitted to the rotation unit once the drive gear
has meshed with the toothing on the rotation unit.
[0046] In yet another embodiment of the invention, a transmitting
gear may be provided between the drive gear and the toothing on the
rotation unit. This embodiment has the advantage that adapting the
diameters of the drive and transmitting gears will allow a simple
setting of different rotary speed ratios. Furthermore, a
transmitting gear will yield increased flexibility as far as the
arrangement of the sample containers on the centrifuge rotor is
concerned.
[0047] It is considered particularly advantageous to design the
centrifuge as a dual symmetrical centrifuge. This has the advantage
that the processing volume will be increased owing to the presence
of at least two rotation units, in particular rotatable centrifuge
containers, as compared to one dual asymmetric centrifuge.
Asymmetric centrifuges moreover have the disadvantage that they
need to entrain a dummy weight so as to compensate for unbalances.
Precise adjustment as is particularly required for higher rotary
speeds is complex and moreover limiting since the dummy is
pre-defined and the weight on the side of the samples must not
exceed the weight of the dummy. If the weight of the sample is
lower than that of the dummy, balancing weights need to be
provided. Great care must be taken here since this might otherwise
result in unbalance.
[0048] According to yet another aspect of the invention, an
apparatus for the homogenization and separation of media is
provided which includes means which can be used to set at least two
different rotary speeds of the rotation unit.
[0049] In similar DC processes such as the production of small
amounts of liposomes in different vessels, clearly different
process parameters need to be applied, in particular a different
ratio of main rotation to secondary rotation.
[0050] The prior art devices have the disadvantage that they do not
allow the setting of optimal conditions for a defined DC process,
as they are required for example for homogenization for the
production of nanoparticles. In this case, the process parameters
need to be adapted and adjusted with regard to their mutual ratios
and with regard to the sample amount to the ratio of main rotation
and reverse rotation.
[0051] It is the object of the invention to provide an apparatus
which allows optimal adjustment of the conditions for different DC
processes.
[0052] This object is accomplished by the characterizing features
of claim 1 or 5 in combination with the features of its respective
preamble.
[0053] In order to improve on a dual centrifuge device, the
apparatus of the invention comprises in a known manner a centrifuge
having a centrifuge rotor which can be rotated about a motor axis
of a centrifuge motor. At least one rotation unit can be mounted on
said centrifuge rotor in such a way that the former is mounted so
as to be rotatable about a secondary axis of rotation which is
different from the axis of the motor.
[0054] The invention is characterized in that means are provided
which can be used to set at least two different rotary speeds of
the rotation units. The rotation of the rotation units about the
secondary axis of rotation is also referred to as reverse
rotation.
[0055] It has surprisingly been found that parameters such as
amount and material ratio can be compensated by adjusting the speed
of rotation. This makes it possible to maintain these parameters
and still yield ideal results in dual centrifugation processes.
[0056] Such more precise adjustment of the reverse rotation speed
and/or the ratio of main rotation to reverse rotation now also
allows use of an apparatus for dual centrifugation for performing
sensitive processes which previously could not be handled by dual
centrifugation apparatus.
[0057] For example in pharmaceutical development, where DC
processes need to be performed and/or optimized with smaller
amounts of samples first and with larger quantities later on,
various DC apparatuses need to be available. Holding various DC
apparatuses ready is not only costly but also takes up a lot of
precious laboratory space.
[0058] In particular, means are formed such that a defined ratio of
main rotation to reverse rotation can be set, said means being
provided in the form of a mechanical coupling which can be used to
vary the ratio of main rotation to reverse rotation in a fast and
easy manner. The mechanical coupling is accomplished in particular
via a gear connection which allows the setting of a precise and
reproducible reverse rotation ratio. The rotation unit drive
comprises toothing which is connected to the centrifuge motor.
[0059] Preferably these means are designed such that a central
sprocket which is rigid with respect to the motor axis can be
mounted on the motor casing. The centrifuge rotor has a pair of
gears, the first gear of which engages the sprocket mounted on the
motor casing. The second gear meshes with the toothing provided on
the rotation unit. Owing to the size ratios of the central sprocket
and the pair of gears, different transmission ratios of main
rotation to reverse rotation may thus be implemented by simply
exchanging the centrifuge rotor and the central sprocket.
[0060] In an embodiment that is considered particularly
advantageous, the means for adjusting the reverse rotation speed
are designed such that they allow the reverse rotation speed to be
changed during centrifugation.
[0061] In particular, the reverse rotation speed and/or the ratio
of main rotation to reverse rotation may be set continuously or
incrementally, it may depend directly on the main rotary motion or
may be adjusted via a variable transmission or may be adjustable
independently of the latter.
[0062] There may also be two secondary axes of rotation, and the
directions of rotation of these two axes of rotation can be chosen
as desired. Depending on the specific application, the axes of
rotation may either both rotate in the same direction or in
opposite directions (relative to the main rotation).
[0063] In accordance with the present invention, only one means for
rotating the rotation units about a secondary axis of rotation may
be provided. However, there may also be plural means which are
arranged symmetrically.
[0064] In this case, the rotations about the secondary axes of
rotation may be synchronous or also uniform, the arrangement
(position, angle to the main axis of rotation) of the secondary
axes of rotation may be chosen as desired, with a rotationally
symmetrical arrangement being preferred, however.
[0065] One way of adapting the speed of rotation of the rotation
unit is by using a DC exchangeable turret with different ratios
between main rotation and secondary rotation. An exchangeable
turret preferably has a fixed transmission means which transmits
the rotary motion of the centrifuge rotor to the rotation unit at a
fixed ratio.
[0066] The connection unit between the centrifuge rotor and the
centrifuge motor is designed such that rotors having different
transmission means with different transmission ratios can be
exchanged easily on the centrifuge motor. Besides affording a
certain degree of flexibility in the adjustment of the rotation
speed, the use of an exchangeable turret also has the advantage
that the amount to be processed and/or the container size can be
varied as a function of the exchangeable turret used in each case.
This saves expensive laboratory space, as one basic device can be
used for different requirements. Moreover, an appropriate basic
device can also be used as a conventional centrifuge.
[0067] In particular, an apparatus of the present invention has a
stationary sprocket which is non-rotatably connected to the
centrifuge housing. As transmission means, at least one pair of
gears may be provided. In the mounted state, a first gear thereof
will mesh with the stationary sprocket, and a second gear thereof
will engage the rotation unit.
[0068] In a first alternative embodiment, the centrifuge rotor may
include a first gear which is matched to a standardized sprocket.
The diameter ratio of the first gear to the second gear will
determine a fixed ratio of main rotation to reverse rotation with
respect to the centrifuge rotor.
[0069] According to another alternative embodiment, the toothing
provided on the rotation unit may directly engage a gear provided
on the centrifuge motor. The rotary speed ratios may be adapted by
exchanging the gear and the rotation units.
[0070] This thus allows the ratio of main rotation to reverse
rotation to be changed by simply exchanging the centrifuge
rotor.
[0071] According to a second alternative embodiment, the sprocket
which is non-rotatably mounted may be exchangeable. The fact that
the non-rotatably mounted sprocket can be exchanged allows the
diameter of this sprocket to be adjusted to the diameter of a first
exchangeable gear of a pair of transmitting gears. Adjusting the
diameter of the sprocket to the first gear of the pair of
transmitting gears is a simple way of adjusting the ratio of main
rotation to reverse rotation without having to provide plural DC
rotors.
[0072] An improvement is achieved by designing the rotation unit
such that its speed of rotation can be adjusted at the same main
speed of rotation without having to make a substantial structural
change to the actual apparatus. The container drive will thus be
capable of realizing at least two different speeds at the same main
speed of rotation. The fact that the speed of rotation about a
secondary axis of rotation can be adjusted allows for a significant
increase of the scope of application of a DC apparatus.
[0073] A special advantage is obtained by decoupling the rotary
speed of the centrifuge motor from that of the container drive so
that the container may also reach a negative speed with respect to
the rotor. This corresponds to switching between forward and
reverse rotation of the container relative to the main rotation of
the rotor. Amongst other things, this will allow two different
homogenization or mixing modes to be accomplished in one DC
process, if for example the inner surface of the container is
designed such that the material to be homogenized or mixed will be
exposed to a different kind of friction each--depending on the
direction of rotation. This may be accomplished by providing a
directionally structured surface.
[0074] In yet another advantageous embodiment, the rotation unit
can be connected to a drive gear, in particular the central gear,
via a freewheel. In this way, the rotary motion will only be
transmitted in one direction of rotation. Accordingly, the
freewheel can be used to mechanically decouple the rotary motion of
the container, by reversing the main direction of rotation. This
has the advantage that the rotary motion of the container can be
interrupted so as to allow a separation or concentration process to
be initiated following a mixing or homogenization DC process. In
yet another embodiment, a central gear may be connected to the main
rotor via coupling means in such a way that the central gear can be
non-rotatably mounted, if required, by means of catch means. If
required, this will thus allow the gear to be decoupled before the
centrifuge axis. Consequently, the rotation will no longer be
transmitted to the rotation units, thus ensuring a pure
centrifugation of the samples.
[0075] A particular advantageous implementation of the adaptability
of the rotary speed of the containers can be achieved by connecting
the rotation unit drive to the centrifuge motor via a conventional
transmission. The switch-over can be performed mechanically during
non-operation of the apparatus, or the conventional transmission
can be formed as an electrically operated transmission. An
electrically operated transmission can also be used as a simple
means of changing the rotary speed even during operation.
[0076] In particular, where there are plural rotation units, these
are coupled in pairs with respect to their speeds. For example, for
a total of four rotation units, two opposing rotation units may
thus be operated at a certain transmission ratio, whilst the other
two opposing rotation units may be operated at a different
transmission ratio.
[0077] In a particularly advantageous embodiment, the transmission
may be incorporated in the DC rotor of the centrifuge. Switching
the transmission may for example be accomplished through an
electrical circuit, with the energy for switching the transmission
being derived from the rotation of the centrifuge rotor.
[0078] In an alternative embodiment, the transmission may also be
incorporated in the rotation unit to be inserted in the centrifuge
rotor, however. This has the advantage that the rotary speeds or
speed ranges can be determined depending on the rotation unit
inserted.
[0079] It is also possible to switch a transmission that has been
inserted in a rotation unit.
[0080] In yet another advantageous embodiment, the rotation unit
drive is connected to a rotation unit motor which is independent of
the centrifuge motor. This yields the advantage that the speed of
rotation can be varied over a clearly vaster range than is possible
when a mechanical transmission is used. Moreover, the rotation
speed can be varied continuously which thus allows an optimum
adaptation to the DC process. In addition, this also allows a
reversal of the direction of rotation, or a complete switch-off, of
the secondary rotation.
[0081] This motorized drive of the rotation unit may preferably be
incorporated in the centrifuge rotor. The electric motor for
driving the secondary rotation may preferably be controlled through
contactless transmission of energy and signals. For the contactless
transmission of energy, a transmitter is provided which may take
the form of a generator, for example, and which will provide energy
on the side of the rotor through the relative motion between the
rotor and the centrifuge. Alternatively, sliding contacts may also
be used for the transmission of energy.
[0082] Owing to this energy and signal transmission, a temperature
sensor can be incorporated in the vicinity of the sample container.
The presence of a temperature sensor in combination with the signal
transmission to the main rotor allows a temperature-based control
of main rotation and secondary rotation. Adjusting the main
rotation and the secondary rotation allows the sample temperature
to be adjusted which thus ensures that also heat-sensitive samples
can be processed reliably. Furthermore, it is also possible for
example to display the temperature on a display means provided on
the apparatus or to output the temperature data acquired over the
operating time at an interface provided for this purpose. This kind
of documentation may thus also provide evidence that the sample has
not exceeded a certain maximum temperature over the entire
centrifugation time.
[0083] Preferably a combination of two to four rotation units
driven by two rotation unit motors may be used. The two rotation
unit motors are symmetrically mounted in the rotor. According to
the prior art, contactless energy transmission by way of a
transmitting unit will only allow a limited amount of power to be
transmitted. However, the provision of two motors makes it possible
to use two transmitting units which thus increases the driving
power per rotation unit.
[0084] However, in yet another embodiment, only one container motor
may be used for driving the rotation units of preferably two to
four rotation units. The rotation unit motor will then in
particular be coaxially mounted on the rotor with respect to the
main axis of rotation for which reason it will only be exposed to a
limited extent to the centrifugal forces.
[0085] The electromotive drive may be connected to the main drive
by means of a mechanical coupling via a gear transmission or a V
belt, as in the case of the mechanical drive. In addition, toothing
may in particular also be provided on the rotation unit.
[0086] In a particularly advantageous embodiment, the electric
drive motor for the rotation unit may be in the form of a stepper
motor. Using a stepper motor allows the containers to be positioned
more precisely. This is beneficial for the performance of a DC
process in which a mixing process is to be combined with a
separation, as is the case for example in a liquid-liquid
extraction or a liquid-solid extraction.
[0087] In yet another advantageous embodiment, the holding fixture
may include entrainment means for locking or fixing the reduction
means or sample containers with respect to the holding fixture.
This on the one hand ensures reliable positioning during the
centrifugation and/or mixing process; on the other hand it also
ensures that the reduction means or containers are fixed in the
direction of rotation. Preferably, the sample may also be held in
the centrifuge container by means of a separate sample vessel. This
may be accomplished by way of an adapter which is specifically
adapted to the centrifuge container.
[0088] A particularly advantageous application of the above
mentioned invention is in a process for producing
nanoparticles.
[0089] Further advantages, features and potential applications of
the present invention may be gathered from the description which
follows, in conjunction with the embodiments illustrated in the
drawings.
[0090] Throughout the description, the claims and the drawings,
those terms and associated reference signs will be used as are
notable from the enclosed list of reference signs. In the drawings
is shown
[0091] FIG. 1 a sectional view of an apparatus according to the
invention, in which the rotation units provided with toothing are
driven by a central gear;
[0092] FIG. 2 a top view of the apparatus of FIG. 1;
[0093] FIG. 3 a sectional view of an apparatus according to the
invention, in which the rotation units provided with toothing are
driven by a central gear, via a pair of transmitting gears;
[0094] FIG. 4 a top view of the apparatus of FIG. 3;
[0095] FIG. 5 a top view of configurations of the central gear and
the transmitting gear;
[0096] FIG. 6 a sectional view of the rotor body and the rotation
unit which latter is accommodated in a recess in the rotor
body;
[0097] FIG. 7 a sectional view of an apparatus, with a central
electric motor being provided for driving the rotation units;
[0098] FIG. 8 a top view of the apparatus of FIG. 7;
[0099] FIG. 9 a sectional view of the rotor body and of the
rotation unit which latter is accommodated in a recess in the rotor
body, and
[0100] FIG. 10 a chart of measurement results regarding the quality
of dispersion in the production of liposomes under different
conditions.
[0101] The view of FIG. 1 shows a dual centrifuge 10 for the
homogenization and separation of media, comprising a centrifuge
motor 12 and a centrifuge rotor 14. The centrifuge rotor 14 rotates
about an axis A which corresponds to the drive axle of the
centrifuge motor 12. The centrifuge rotor 14 is connected to
rotation units 16 which are mounted so as to be rotatable about
their axes of rotation R1, R2. The rotation units 16 have gear
teeth 18 on their peripheral sections which mesh with a gear 22
which is non-rotatably mounted on the centrifuge motor housing 20.
Rotation of the centrifuge rotor 14 about the motor axis A with
respect to the motor 12 will cause the rotation units 16 to rotate
about their rotation unit axis R. Each rotation unit 16 is mounted
in the centrifuge rotor 14 in a recess 30 specifically provided in
the centrifuge rotor 14 for this purpose, into which two bearings
24, 26, which take the form of angular contact ball bearings, per
rotation unit 16 have been inserted. Via their outer rings, these
angular contact ball bearings are supported on the recess in the
centrifuge rotor 14. The inner ring of each bearing is connected to
the shaft 16a of the rotation unit 16. The recess 30 provided in
the body of the centrifuge rotor 14 is designed so as to be closed
at its base, in particular to be cup-shaped. This design of the
holding fixture of the rotation unit 16 makes it possible to retain
any lubricant leaking from the bearing 24, 26 within the centrifuge
unit and/or the centrifuge rotor 14 and thus to ensure lubrication
of the ball bearings 24, 26 even if the lubricant has exited the
actual bearing 24, 26.
[0102] The centrifugal force occurring during rotation of the
centrifuge rotor 14 will urge the lubricant toward the radially
outer "cup" edge of the cup-shaped recess 30 where it will then
collect. In this way, the ball bearings 24, 26 can still be
continuously lubricated in operation, using lubricant that has
already leaked out. This allows a high rotation speed both of the
centrifuge rotor 14 and the rotation unit 16 to be achieved at long
run times.
[0103] Furthermore, as in shown in FIG. 1, the rotation unit 16 has
its shaft 16a extending through the ball bearings 24, 26, with a
clamping ring 32 provided on the end of the shaft 16a which clamps
the ball bearings 24, 26 in position with respect to the rotation
unit 16. Furthermore, mounted on the top of the body of the
centrifuge rotor 14 and/or on the top of the cup-shaped recess 30
is a plate 34 which will retain the ball bearing array within the
rotor body. In addition, this constitutes some kind of cover in
order to prevent the leaking out of lubricants from the centrifuge
cup during centrifugation.
[0104] FIG. 2 is a top view of the centrifuge rotor 14 of FIG. 1.
As can clearly be seen from this view, the rotor 14 has two
rotation units 16 extending in a first axis, each having a cage 28
screwed onto it. At least one sample vessel containing material to
be centrifuged can be inserted into said cage 28. In the axis
extending orthogonally to the first axis, there are two spaces for
pure centrifugation purposes. Centrifugation containers placed in
these spaces cannot be rotated about their own axis.
[0105] FIG. 3 is a sectional view of a centrifuge 40 for the
homogenization and separation of media in which the reverse
rotation speed of the rotation units 48 can be set in a simple
manner. The centrifugation apparatus 40 comprises a centrifuge
motor 42 which rotates about the motor axis A. A centrifuge rotor
44 can be mounted on the centrifuge motor 42 by means of a bolted
connection. Cup-shaped recesses 46 are provided in the body of the
centrifuge rotor 44. These cup-shaped recesses 46 will accommodate
rotation units 48 for dual centrifugation. The structure of these
rotation units 48 will be described in more detail below with
respect to FIG. 6. A central gear 50, which is non-rotatably
mounted with respect to the centrifuge rotor 44, is provided for
transmitting the rotary motion about the rotation axis R1, R2 of
the rotation units 48. This gear 50 can be easily connected to the
non-rotatably mounted motor casing, for example by means of a
bolted connection, after the centrifuge rotor 44 has been
removed.
[0106] Furthermore, for transmitting the relative rotary motion
between the rotor 44 and the centrifuge motor 42, pairs 52 of gears
are provided, with one pair 52 of gears comprising a first gear 54
which meshes with the central gear 50, and a second gear 56 which
engages the toothing on the rotation unit 48. The ratio of main
rotation to reverse rotation is thus defined by the transmission
ratio of the gear array 50, 54, 56. In view of the fact that the
gears 54, 56 of the pair 52 of gears can be exchanged easily, the
speed ratio can also be changed easily by simply adapting the
diameters of the gears 54 and the central gear 50 which is
engagement with it. One example for gear configurations 50, 54 for
different speed transmissions is shown in FIG. 5. Adapting the
reverse rotation speed of the rotation units 48 can thus be
achieved in an easy way by exchanging a mere three components.
Furthermore, if one replaces the rotor, the centrifuges can also be
used as a "normal" centrifuge.
[0107] FIG. 4 is a top view of a centrifuge rotor according to FIG.
3, which quite clearly shows the first gear 56 of the pair 52 of
gears as it meshes with the toothing provided on the rotation unit
48. Furthermore, cooling means 58 are provided on the rotor, in the
form of cooling fins or recesses so as to increase the surface for
improved heat dissipation. As in the embodiment of FIG. 1, some
additional centrifugation spaces 60 are also provided here for
"normal" centrifugation.
[0108] FIG. 5 is a view of two sets of a central gear 50a, 50b and
of the gear 54a, 54b of the gear pair driving the rotation unit,
which gear 54a, 54b meshes with said central gear 50a, 50b. It can
be understood quite well from the view of FIG. 5 how changing the
gear diameter of the central gear 50a, 50b and of the first gear
54a, 54b of the transmitting gears allows the speed ratio to be
adjusted without having to vary the centre distance X. Exchanging
these two components constitutes an easy way of changing the ratio
of main rotation to reverse rotation.
[0109] FIG. 6 is an enlarged view illustrating how the rotation
unit 48 is accommodated within the rotor body 44. The rotor body 44
has a cup-shaped recess 46 for accommodating the rotation unit 48.
This recess houses a ball bearing, in particular an angular contact
ball bearing 60. A retaining plate 62 is used to brace this bearing
with respect to the rotation unit 48. Moreover, disposed at the top
of the recess 46 is a sliding contact bearing 64 for mounting the
rotation unit 48. The cup-shaped recess 46 in the rotor body 44 is
designed such that any lubricant exiting the ball bearing during
centrifugation will collect in the radially outer portion of the
centrifuge rotor 44 at the level of the ball bearing and thus
provide lubrication for these components. Consequently, high
rotation speeds and thus accordingly high centrifugal forces can be
provided. This continuous lubrication cycle also ensures long run
times of the centrifuge.
[0110] FIG. 7 is a view of a dual centrifuge 70 having a variable
reverse rotation speed. Typically, this centrifuge has a centrifuge
motor 72 onto which a centrifuge rotor 74 has been placed. The
centrifuge rotor 74 of this embodiment comprises an additional
rotation unit motor 76 which is provided with a drive gear 78 which
in turn meshes with the toothing of the rotation unit 80 and thus
ensures corresponding rotation of the rotation unit 80 about the
rotation unit axis R1, R2. The reverse rotation speed of the
rotation units 80 depends on the speed of rotation of the rotation
unit motor 76. Energy transmission for the rotation unit motor 76
is in particular wireless. The fact that the use of the electric
motor as an independent rotation unit motor 76 allows the rotation
speed to be adjusted and varied not only irrespective of the speed
of rotation of the centrifuge rotor 74 but also during actual
operation, makes it possible to implement a wide variety of
applications. What is considered particularly advantageous is that
adapting the speed of rotation, in particular the speed of reverse
rotation, during operation also allows sample temperature control.
This will be explained in more detail below with reference to FIG.
9.
[0111] FIG. 8 is a top view of the centrifuge rotor 74 which
clearly shows how the toothing provided on the rotation units 80
meshes with the teeth of the drive gear 78 which is connected to
the rotation unit drive motor 76.
[0112] FIG. 9 is an enlarged view of the embodiment illustrated in
FIGS. 7 and 8. This design essentially corresponds to a rotor 74 in
which an essentially cup-shaped recess 84 has been provided, the
bottom of which forms a collection tray for the lubricant. Mounted
within said cup-shaped recess 84, the one on top of the other, are
two angular contact bearings 86, 88. These bearings are connected
to the rotation unit 80 via a clamping ring 90 with largely no play
between these components. The outer rings of the ball bearings 86,
88 are held within the cup-shaped recess 84 by a retaining plate 92
which is screwed to the centrifuge rotor. The rotation unit is thus
firmly connected to the centrifuge rotor 74 in an axial direction.
In this embodiment, the bottom of the cup-shaped recess 84 has a
cylindrical raised portion which projects into a recess of the
shaft of the rotation unit. This cylindrical raised portion ensures
that the lubricant collection tray of the cup-shaped recess 84 has
an essentially annular base. Mounted within said cylindrical raised
portion 94 is a temperature sensor which is adapted to measure the
temperature of the material to be centrifuged. Depending on the
temperature thus measured, the rate and speed of rotation of the
rotation units 80 may be modified such that a certain desired
temperature can be set. The rotation unit is connected to a
cage-like holding fixture 96 which has recesses in the form of
holes so as to ensure improved heat dissipation from the heated
sample. This holding fixture 96 will receive sample vessels or
adapters and/or reduction means into which sample vessels have in
turn been inserted.
[0113] FIG. 10 illustrates the specific application of producing
liposomes at different speed ratios between main rotation and
reverse rotation.
[0114] The subject of this examination was the production of
liposomes through homogenization (30 min each) of a molecularly
dispersed mixture of hydrated egg yolk phosphatidylcholine and
cholesterol (55:45 mol/mol) with 60 wt.-% of water and the addition
of 100 wt.-% of glass beads (1 mm). The DC homogenization process
was examined for 10 ml PP vials (43.3 mm long and 23 mm wide),
glass injection vials (50 ml, 42 mm in diameter) and 2 ml plastic
vials (twist top vials).
[0115] Using the DC apparatus of the present invention with an
exchangeable rotor of FIG. 3 in a standard Hettich Rotanta 460R
type centrifuge, it was possible to set and examine different
ratios of main rotation and secondary rotation (1:1.43, 1:2.1,
1:3.5). The results are shown in the chart. The DC homogenization
process was conducted at a main rotation rate of 3,500 rpm.
[0116] The results indicate that--despite the similarity of the
experiments (same DC homogenization process, same lipids, same
homogenization aids etc.)--the use of different sample vessels
already yielded clearly different ratios of main rotation and
secondary rotation for the production of as small as possible
liposomes with an as narrow as possible size distribution (low PI
value). The desired, as small as possible liposomes having a low PI
value are obtained in the PP vials, in particular at medium
transmission ratios. This also applies to the use of the 2 ml
plastic vials (twist top vials). By contrast, when using the 50 ml
glass injection vials, smaller liposomes are preferably formed at
higher transmission ratios.
[0117] This shows that there is no general optimal ratio between
main rotation and secondary rotation for a certain DC process but
that the optimum ratio will always have to be adapted to the
specific conditions (in this case the type of vial). This clearly
illustrates how important it is to be able to adjust the ratio of
main rotation and secondary rotation, in particular for the
production of liposomes.
LIST OF REFERENCE SIGNS
[0118] 10 dual centrifuge [0119] 12 centrifuge motor [0120] 14
centrifuge rotor [0121] 16 rotation unit [0122] 16a shaft [0123] 18
toothing [0124] 20 centrifuge motor housing [0125] 22 gear [0126]
24 bearing [0127] 26 bearing [0128] 28 cage [0129] 30 recess [0130]
32 clamping ring [0131] 34 plate [0132] 40 centrifuge [0133] 42
centrifuge motor [0134] 44 centrifuge rotor [0135] 46 recess [0136]
48 rotation unit [0137] 50 gear [0138] 50a gear [0139] 50b gear
[0140] 52 pair of gears [0141] 54 gear [0142] 54a gear [0143] 54b
gear [0144] 56 gear [0145] 58 cooling means [0146] 60
centrifugation space [0147] 62 retaining plate [0148] 64 sliding
contact bearing [0149] 70 centrifuge [0150] 72 centrifuge motor
[0151] 74 centrifuge rotor [0152] 76 rotation unit motor [0153] 78
drive gear [0154] 80 rotation unit [0155] 84 recess [0156] 86
angular contact bearing [0157] 88 angular contact bearing [0158] 90
clamping ring [0159] 92 retaining plate [0160] 94 raised portion
[0161] 96 holding fixture [0162] A axis [0163] R1 axis of rotation
[0164] R2 axis of rotation
* * * * *